Farnesyl transferase inhibiting 6-heterocyclylmethyl quinoline and quinazoline derivatives

ABSTRACT

This invention comprises the novel compounds of formula (I)  
                 
 
     wherein r, t, Y 1 -Y 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  have defined meanings, having farnesyl transferase inhibiting activity; their preparation, compositions containing them and their use as a medicine.

[0001] The present invention is concerned with novel 6-heterocyclylmethyl quinoline and quinazoline derivatives, the preparation thereof, pharmaceutical compositions comprising said novel compounds and the use of these compounds as a medicine as well as methods of treatment by administering said compounds.

[0002] Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cells leads to cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non-transformed cells. Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer. A particular group of oncogenes is known as ras which have been identified in mammals, birds, insects, mollusks, plants, fungi and yeasts. The family of mammalian ras oncogenes consists of three major members (“isoforms”): H-ras, K-ras and N-ras oncogenes. These ras oncogenes code for highly related proteins generically known as p21^(ras). Once attached to plasma membranes, the mutant or oncogenic forms of p21^(ras) will provide a signal for the transformation and uncontrolled growth of malignant tumor cells. To acquire this transforming potential, the precursor of the p21^(ras) oncoprotein must undergo an enzymatically catalyzed farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Therefore, inhibitors of the enzymes that catalyzes this modification, i.e. farnesyl transferase, will prevent the membrane attachment of p21^(ras) and block the aberrant growth of ras-transformed tumors. Hence, it is generally accepted in the art that farnesyl transferase inhibitors can be very useful as anticancer agents for tumors in which ras contributes to transformation.

[0003] Since mutated oncogenic forms of ras are frequently found in many human cancers, most notably in more than 50% of colon and pancreatic carcinomas (Kohl et al., Science, vol 260, 1834-1837, 1993), it has been suggested that farnesyl tranferase inhibitors can be very useful against these types of cancer.

[0004] In EP-0,371,564 there are described (1H-azol-1-ylmethyl) substituted quinoline and quinolinone derivatives which suppress the plasma elimination of retinoic acids. Some of these compounds also have the ability to inhibit the formation of androgens from progestines and/or inhibit the action of the aromatase enzyme complex.

[0005] In WO 97/16443, WO 97/21701, WO 98/40383 and WO 98/49157, there are described 2-quinolinones and 2-quinazolinones derivatives which exhibit farnesyl transferase inhibiting activity. WO 00/39082 describes a class of novel 1,2-annelated quinoline compounds, bearing a nitrogen- or carbon-linked imidazole, which show farnesyl protein transferase and geranylgeranyl transferase inhibiting activity. Other quinolone compounds having farnesyl transferase inhibiting activity are described in WO 00/12498, 00/12499 and 00/47574.

[0006] Unexpectedly, it has been found that the present novel 6-heterocyclylmethyl quinoline and quinazoline compounds show farnesyl protein transferase inhibiting activity.

[0007] The present invention concerns compounds of formula (I):

[0008] or a pharmaceutically acceptable salt or N-oxide or stereochemically isomeric form thereof, wherein

[0009] r is 0, 1, 2, 3, 4 or 5;

[0010] t is 0, 1, 2 or 3;

[0011] >Y¹-Y²—is a trivalent radical of formula >C═N— (y-1) >C═CR⁹— (y-2) >CH—NR⁹— (y-3) >CH—CHR⁹— (y-4)

[0012] wherein R⁹ is hydrogen, halo, cyano, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkyloxy, halocarbonyl, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, aryl or a group of formula —NR²²R²³, —C₁₋₆alkyl-NR²²R²³, —C₂₋₆alkenyl-NR²²R²³, —CONR²²R²³ or —NR²²—C₁₋₆alkyl-NR²²R²³;

[0013] p is 0 to 5;

[0014] R²⁰ and R²¹ are independently hydrogen or C₁₋₆ alkyl and are independently defined for each iteration of p in excess of 1;

[0015] R²² and R²³ are independently hydrogen, C₁₋₆ alkyl or —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, or together with the adjacent nitrogen atom form a 5- or 6-membered heterocyclic ring optionally containing one, two or three further heteroatoms selected from oxygen, nitrogen or sulphur and optionally substituted by one or two substituents each independently selected from halo, hydroxy, cyano, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, aminocarbonyl, mono- or di-(C₁₋₆alkyl)aminocarbonyl, amino, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkylsulfonylamino, oxime, or phenyl;

[0016] R¹ is azido, hydroxy, halo, cyano, nitro, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, hydroxycarbonylC₁₋₆alkyloxyC₁₋₆alkyl, R²⁴S C₁₋₆alkyl, trihalomethyl, arylC₁₋₆alkyl, Het²C₁₋₆alkyl, —C₁₋₆alkyl-NR²²R²³, —C₁₋₆alkylNR²²C₁₋₆alkyl-NR²²R²³, —C₁₋₆alkylNR²²COC₁₋₆alkyl, —C₁₋₆alkylNR²²COAlkAr², —C₁₋₆alkylNR²²COAr², C₁₋₆alkylsulphonylaminoC₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, —OC₁₋₆alkyl-NR²²R²³, trihalomethoxy, arylC₁₋₆alkyloxy, Het²C₁₋₆alkyloxy, C₁₋₆alkylthio, C₂₋₆alkenyl, cyanoC₂₋₆alkenyl, —C₂₋₆alkenyl-NR²²R²³, hydroxycarbonylC₂₋₆alkenyl, C₁₋₆alkyloxycarbonylC₂₋₆alkenyl, C₂₋₆alkynyl, —CHO, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkylcarbonyl, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR²²R²³, —CONR²²—C₁₋₆alkyl-NR²²R²³, —CONR²²—C₁₋₆alkyl-Het², —CONR²²—C₁₋₆alkyl-Ar², —CONR²²—O—C₁₋₆alkyl, —CONR²²—C₁₋₆alkenyl, —NR²²R²³, —OC(O)R²⁴, —CR²⁴═NR²⁵, —CR²⁴═N—OR²⁵, —NR²⁴C(O) NR²²R²³, —NR²⁴SO₂R²⁵, —NR²⁴C(O)R²⁵, —S(O)₀₋₂R²⁴, —SO₂NR²⁴R²⁵, —C(NR²⁶R²⁷)═NR²⁸; —Sn(R²⁴)₃, —SiR²⁴R²⁴R²⁵, —B(OR²⁴)₂, —P(O)OR²⁴OR²⁵, aryloxy, Het²-oxy, or a group of formula

—Z, —CO—Z or —CO—NR^(y)—Z

[0017] in which R^(y) is hydrogen or C₁₋₄alkyl and Z is phenyl or a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from oxygen, sulphur and nitrogen, the phenyl or heterocyclic ring being optionally substituted by one or two substituents each independently selected from halo, cyano, hydroxycarbonyl, aminocarbonyl, C₁₋₆alkylthio, hydroxy, —NR²²R²³, C₁₋₆alkylsulphonylamino, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkyloxy or phenyl; or

[0018] two R¹ substituents adjacent to one another on the phenyl ring may form together a bivalent radical of formula —O—CH₂—O— (a-1) —O—CH₂—CH₂—O— (a-2) —O—CH═CH— (a-3) —O—CH₂—CH₂— (a-4) —O—CH₂—CH₂—CH₂— (a-5) —CH═CH—CH═CH— (a-6)

[0019] R²⁴ and R²⁵ are independently hydrogen, C₁₋₆ alkyl, —(CR₂₀R₂₁)p-C₃₋₁₀cycloalkyl or aryC₁₋₆alkyl;

[0020] R²⁶, R²⁷ and R²⁸ are independently hydrogen and C₁₋₆alkyl or C(O) C₁₋₆alkyl;

[0021] R² is a mono- or bi-cyclic heterocyclic ring containing one or more heteroatoms selected from oxygen, sulphur and nitrogen and optionally substituted by one or two substituents each independently selected from halo, cyano, hydroxy, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR²²R²³, C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR²²R²³, —NR²²R²³, C₁₋₆alkylsulfonylamino, oxime, phenyl or benzyl;

[0022] R³ is hydrogen, halo, cyano, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, haloC₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, arylC₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkylthioC₁₋₆alkyl, hydroxycarbonylC₁₋₆alkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, —C₁₋₆alkyl-NR²²R²³, —C₁₋₆alkyl-CONR²²R²³, arylC₁₋₆alkyl, Het²C₁₋₆alkyl, C₂₋₆alkenyl, —C₂₋₆alkenyl, —C₂₋₆alkenyl NR²²R²³, C₂₋₆alkynyl, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, aryl, or Het²; or a radical of formula —O—R¹⁰ (b-1) —S—R¹⁰ (b-2) —NR¹¹R¹² (b-3) or —N═C R^(10′)R¹¹ (b-4)

[0023] wherein

[0024] R¹⁰ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, arylC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkylcarbonyl, aryl, a group of formula —NR²²R²³R or —C₁₋₆alkylC(O)OC₁₋₆alkyl NR²²R²³, or a radical of formula -Alk-OR¹³ or -Alk-NR¹⁴R¹⁵;

[0025] R^(10′) is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, arylC₁₋₆alkyl, aryl or a group of formula —NR²²R²³;

[0026] R¹¹ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl or arylC₁₋₆alkyl;

[0027] R¹² is hydrogen, hydroxy, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl, arylC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, C₁₋₆alkyloxy, a group of formula —NR²²R²³, C₁₋₆alkylcarbonylamino, C₁₋₆alkylcarbonyl, haloC₁₋₆alkylcarbonyl, arylC₁₋₆alkylcarbonyl, Het²C₁₋₆alkylcarbonyl, arylcarbonyl, C₁₋₆alkyloxycarbonyl, trihalo C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, aminocarbonyl, mono- or di(C₁₋₆alkyl)aminocarbonyl wherein the alkyl moiety may optionally be substituted by one or more substituents independently selected from aryl and C₁₋₆alkyloxycarbonyl substiuents; aminocarbonylcarbonyl, mono- or di(C₁₋di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, or a radical of formula -Alk-OR¹³ or Alk-NR¹⁴R¹⁵; wherein

[0028] Alk is C₁₋₆alkanediyl;

[0029] R¹³ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkyl, aryl or arylC₁₋₆alkyl;

[0030] R¹⁴ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl or arylC₁₋₆alkyl;

[0031] R¹⁵ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl , C₁₋₆alkylcarbonyl, aryl or arylC₁₋₆alkyl;

[0032] R⁴ is a radical of formula

[0033] wherein R¹⁶ is hydrogen, halo, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkylS(O)₀₋₂C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, a group of formula —NR²²R²³, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl or aryl,

[0034] R¹⁷ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aryl C₁₋₆alkyl, trifluoromethyl, trifluoromethylC₁₋₆alkyl, hydroxycarbonylC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminosulphonyl or —C₁₋₆alkylP(O)OR²⁴OR²⁵;

[0035] R¹⁸ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl , arylC₁₋₆alkyl or C₁₋₆alkyloxyC₁₋₆alkyl;

[0036] R^(18a) is hydrogen, —SH or —SC₁₋₄alkyl;

[0037] R⁵ is cyano, hydroxy, halo, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkyloxy, arylC₁₋₆alkyloxy, Het²C₁₋₆alkyloxy, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, or a group of formula —NR²²R²³ or —CONR²²R²³;

[0038] R⁶ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, cyanoC₁₋₆alkyl, —C₁₋₆alkylCO₂R²⁴, aminocarbonylC₁₋₆alkyl or —C₁₋₆alkyl-NR²²R²³, R²⁴SO₂, R²⁴SO₂C₁₋₆alkyl, —C₁₋₆alkyl-OR²⁴, —C₁₋₆alkyl-SR²⁴, —C₁₋₆alkylCONR²²—C₁₋₆alkyl-NR²²R²³, —C₁₋₆alkylCONR²²—C₁₋₆alkyl-Het², —C₁₋₆alkylCONR²²—C₁₋₆alkyl-Ar², —C₁₋₆alkyl CONR²²-Het², —C₁₋₆alkylCONR²²Ar², —C₁₋₆alkylCONR²²—O—C₁₋₆alkyl, —C₁₋₆alkylCONR²²—C₁₋₆alkenyl, -Alk-Ar² or -AlkHet²;

[0039] R⁷ is oxygen or sulphur; or R⁶ and R⁷ together form a trivalent radical of formula: —CR³⁰═CR³¹—N═ (x-1) —CR³⁰═CR³¹—CR³²═ (x-6) —CR³⁰═N—N═ (x-2) —CR³⁰═N—CR³¹═ (x-7) —C(═O)—NH—N═ (x-3) —C(═O)—NH—CR³⁰═ (x-8) —N═N—N═ (x-4) —N═N—CR³⁰═ (x-9) or —N═CR³⁰—N═ (x-5) —CH₂—(CH₂)⁰⁻¹—CH₂—N═ (x-10)

[0040] wherein each R³⁰, R³¹ and R³² are independently hydrogen, C₁₋₆ alkyl, —OR²⁴, —COOR²⁴, —NR²²R²³, —C₁₋₆ alkylOR²⁴, —C₁₋₆ alkylSR²⁴, R²³R²²NC₁₋₆alkyl-, —CONR²²R²³, C₂₋₆alkenyl, C₂₋₆alkenylAr², C₂₋₆alkenylHet², cyano, amino, thio, C₁₋₆ alkylthio, —O—Ar², —S—Ar² or Ar²;

[0041] Ar² is phenyl, naphthyl or phenyl or naphthyl substituted by one to five substituents each independently selected from halo, hydroxy, cyano, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR²²R²³, C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, aryloxy, —NR²²R²³, C₁₋₆alkylsulfonylamino, oxime or phenyl, or a bivalent substituent of formula —O—CH₂—O— or —O—CH₂—CH₂—O—;

[0042] Het² is a mono- or bi-cyclic heterocyclic ring containing one or more heteroatoms selected from oxygen, sulphur and nitrogen and optionally substituted by one or two substituents each independently selected from halo, hydroxy, cyano, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR²²R²³, C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR²²R²³, —NR²²R²³, C₁₋₆alkylsulfonylamino, oxime or phenyl;

[0043] provided that when >Y¹-Y² is a radical of formula (y-2) or (y-4) and (a) R⁴ is a radical of formula (c-1), (c-2) or (c-4) and/or (b) R² is an optionally substituted imidazolyl or pyridyl group, then R⁷ is not oxygen or sulphur.

[0044] As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C₁₋₄alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, e.g. methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and the like; C₁₋₆alkyl includes C₁₋₄alkyl and the higher homologues thereof having 5 to 6 carbon atoms such as, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; C₁₋₆alkanediyl defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof; haloC₁₋₆alkyl defines C₁₋₆alkyl containing one or more halo substituents for example trifluoromethyl; C₂₋₆alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 2 to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, and the like. The term “S(O)” refers to a sulfoxide and “S(O)₂” to a sulfone. Aryl defines phenyl, naphthalenyl or phenyl substituted with one or more substituents each independently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy or trifluoromethyl, cyano, hydroxycarbonyl.

[0045] The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The compounds of formula (I) which have basic properties can be converted in their pharmaceutically acceptable acid addition salts by treating said base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-amino-salicylic, pamoic and the like acids.

[0046] The term acid addition salts also comprises the hydrates and the solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.

[0047] The term stereochemically isomeric forms of compounds of formula (I), as used hereinbefore, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of formula (I) both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.

[0048] Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.

[0049] Whenever used hereinafter, the term “compounds of formula (I)” is meant to include also the pharmaceutically acceptable acid addition salts and all stereoisomeric forms.

[0050] Examples of compounds of formula (I) include those wherein one or more of the following restrictions apply:

[0051] r is 0, 1 or 2;

[0052] t is 0 or 1;

[0053] >Y¹-Y²—is a trivalent radical of formula >C═N— (y-1) >C═CR⁹— (y-2)

[0054] wherein R⁹ is hydrogen, cyano, halo, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, hydroxycarbonyl or aminocarbonyl;

[0055] R¹ is halo, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, trihalomethyl, trihalomethoxy, C₂₋₆alkenyl, hydroxycarbonylC₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, aminoC₁₋₆alkyloxy, C₁₋₆alkylthio, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR²²R²³, or —CH═NOR²⁵; or two R¹ substituents adjacent to one another on the phenyl ring may independently form together a bivalent radical of formula —O—CH₂—O— (a-1) —O—CH₂—CH₂—O— (a-2)

[0056] R² is a 5- or 6-membered monocyclic heterocyclic ring containing one, two or three heteroatoms selected from oxygen, sulphur or nitrogen or a 9- or 10-membered bicyclic heterocyclic ring

[0057] R³ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, haloC₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, —C₁₋₆alkyl NR²²R²³, Het²C₁₋₆alkyl, —C₂₋₆alkenyl NR²²R²³, or -Het²; or a group of formula —O—R¹⁰ (b-1) —NR¹¹R¹² (b-3)

[0058] wherein R¹⁰ is hydrogen, C₁₋₆alkyl, or —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, or a group of formula -Alk-OR¹³ or -Alk-NR¹⁴R¹⁵;

[0059] R¹¹ is hydrogen or C₁₋₆alkyl;

[0060] R¹² is hydrogen, hydroxy, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, aminocarbonyl, or a radical of formula -Alk-OR¹³ or Alk-NR¹⁴R¹⁵;

[0061] wherein Alk is C₁₋₆alkanediyl;

[0062] R¹³ is hydrogen, C₁₋₆alkyl or —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl;

[0063] R¹⁴ is hydrogen, C₁₋₆alkyl, or —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl;

[0064] R¹⁵ is hydrogen or C₁₋₆alkyl;

[0065] R⁴ is a radical of formula (c-2) or (c-3)

[0066] wherein R¹⁶ is hydrogen, halo or C₁₋₆alkyl,

[0067] R¹⁷ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₁₋₆alkyloxyC₁₋₆alkyl or trifluoromethyl;

[0068] R¹⁸ is hydrogen, C₁₋₆alkyl or —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl;

[0069] R^(18a) is hydrogen;

[0070] R⁵ is cyano, halo, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkyloxy or C₁₋₆alkyloxycarbonyl:

[0071] R⁶ is hydrogen, C₁₋₆alkyl, —C₁₋₆alkylCO₂R²⁴, —C₁₋₆alkyl-C(O)NR²²R²³, -Alk-Ar², -AlkHet² or —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,

[0072] R⁷ is oxygen; or R⁶ and R⁷ together form a trivalent radical of formula (x-1), (x-2), (x-3), (x-4) or (x-9)

[0073] Het² is a 5- or 6-membered monocyclic heterocyclic ring containing one, two or three heteroatoms selected from oxygen, sulphur or nitrogen for example pyrrolidinyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, furyl, morpholinyl, piperazinyl, piperidinyl, thiophenyl, thiazolyl or oxazolyl, or a 9- or 10-membered bicyclic heterocyclic ring especially one in which a benzene ring is fused to a heterocyclic ring containing one, two or three heteroatoms selected from oxygen, sulphur or nitrogen for example indolyl, benzofuryl, benzothienyl, quinolinyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzothiazolyl or benzodioxolanyl.

[0074] A group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply:

[0075] >Y¹-Y²—is a trivalent radical of formula (y-1) or (y-2), wherein R⁹ is hydrogen, halo, C₁₋₄alkyl, hydroxycarbonyl, or C₁₋₄alkyloxycarbonyl;

[0076] r is 0, 1 or 2;

[0077] t is 0;

[0078] R¹ is halo, C₁₋₆alkyl or two R¹ substituents ortho to one another on the phenyl ring may independently form together a bivalent radical of formula (a-1);

[0079] R² is a 5- or 6-membered monocyclic heterocyclic ring containing one or two heteroatoms selected from oxygen, sulphur or nitrogen or a 9- or 10-membered bicyclic heterocyclic ring in which a benzene ring is fused to a heterocyclic ring containing one, two or three heteroatoms selected from oxygen, sulphur or nitrogen, optionally substituted by halo, cyano, C₁₋₆alkyl or aryl; R³ is Het² or a group of formula (b-1) or (b-3) wherein

[0080] R¹⁰ is hydrogen or a group of formula -Alk-OR¹³.

[0081] R¹¹ is hydrogen;

[0082] R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxy, C₁₋₆alkyloxy or mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl;

[0083] Alk is C₁₋₆alkanediyl and R¹³ is hydrogen;

[0084] R⁴ is a group of formula (c-2) or (c-3) wherein

[0085] R¹⁶ is hydrogen, halo or mono- or di(C₁₋₄alkyl)amino;

[0086] R¹⁷ is hydrogen or C₁₋₆alkyl;

[0087] R¹⁸ is hydrogen or C₁₋₆alkyl;

[0088] R^(18a) is hydrogen;

[0089] R⁶ is —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, —C₁₋₆alkylCO₂R²⁴, aminocarbonylC₁₋₆alkyl, -Alk-Ar² or -AlkHet² or C₁₋₆alkyl;

[0090] R⁷ is oxygen; or R⁶ and R⁷ together form a trivalent radical of formula (x-1), (x-2), (x-3), (x-4) or (x-9)

[0091] aryl is phenyl.

[0092] A particular group of compounds consists of those compounds of formula (I) wherein

[0093] >Y¹-Y² is a trivalent radical of formula (y-1) or (y-2), r is 0 or 1, t is 0, R¹ is halo, C₍₁₋₄₎alkyl or forms a bivalent radical of formula (a-1), R² is a 5- or 6-membered monocyclic heterocyclic ring containing one or two heteroatoms selected from oxygen, sulphur or nitrogen or a 9- or 10-membered bicyclic heterocyclic ring in which a benzene ring is fused to a heterocyclic ring containing one or two heteroatoms selected from oxygen, sulphur or nitrogen, optionally substituted by halo, cyano, C₁₋₆alkyl or aryl.

[0094] R³ is hydrogen or a radical of formula (b-1) or (b-3), R¹⁰ is hydrogen or -Alk-OR¹³, R¹¹ is hydrogen and R¹² is hydrogen or C₁₋₆alkylcarbonyl and R¹³ is hydrogen; R⁴ is a radical of formula (c-2) or (c-3), wherein R¹⁶ is hydrogen, R¹⁷ is C₁₋₆alkyl, R¹⁸ is C₁₋₆alkyl, R^(18a) is hydrogen; R⁶ is C₁₋₆alkyl, —CH₂—C₃₋₁₀cycloalkyl, —C₁₋₆alkylCO₂R²⁴ (R²⁴═H, Et), aminocarbonylC₁₋₆alkyl, -Alk-Ar² or -AlkHet²; and R⁷ is oxygen; or R⁶ and R⁷ together form a trivalent radical of formula (x-2), (x-3) or (x-4).

[0095] More preferred compounds are those compounds of formula (I) wherein >Y¹-Y² is a trivalent radical of formula (y-1) or (y-2), r is 0 or 1, s is 1, t is 0, R¹ is halo, preferably chloro and most preferably 3-chloro, R² is a thiophene, furyl, pyridyl, diazolyl, oxazolyl, benzodiazolyl, benzotriazolyl, or quinolinyl group, optionally substituted by halo preferably chloro, cyano, C₁₋₆alkyl, preferably methyl, or aryl; R³ is hydrogen or a radical of formula (b-1) or (b-3), R⁹ is hydrogen, R¹⁰ is hydrogen, R¹¹ is hydrogen and R¹² is hydrogen; R⁴ is a radical of formula (c-2) or (c-3), wherein R¹⁶ is hydrogen, R¹⁷ is C₁₋₆alkyl, R¹⁸ is C₁₋₆alkyl, R^(18a) is hydrogen; R⁶ is C₁₋₆alkyl, —CH₂—CH₃₋₁₀cycloalkyl or —C₁₋₆alkylAr²; R⁷ is oxygen; or R⁶ and R⁷ together form a trivalent radical of formula (x-2) or (x-4).

[0096] Especially preferred compounds are those compounds of formula (I) wherein >Y¹-Y² is a trivalent radical of formula (y-1) or (y-2), r is 1, t is 0, R¹ is halo, preferably chloro, and most preferably 3-chloro, R² is a 4-chloro-thiophen-2-yl, 3-furyl, 5-chloro-pyrid-3-yl, 2-phenyl-imidazol-1-yl, 2-ethyl-imidazol-1-yl, benzimidazol-1-yl or 2-hydroxy-quinoline-7-yl group; R³ is a radical of formula (b-1) or (b-3), R⁹ is hydrogen, R¹⁰ and R¹¹ are hydrogen and R¹² is hydrogen or hydroxy; R⁴ is a radical of formula (c-2) or (c-3), wherein R¹⁶ is hydrogen, R¹⁷ is C₁₋₆alkyl preferably methyl, R¹⁸ is C₁₋₆alkyl preferably methyl, R^(18a) is hydrogen; R⁶ is C₁₋₆alkyl, —CH₂—C₃₋₁₀cycloalkyl or -alkylAr²; R⁷ is oxygen; or R⁶ and R⁷ together form a trivalent radical of formula (x-4).

[0097] The most preferred compounds according to the invention are:

[0098] 5-(3-chlorophenyl)-α-(5-chloro-2-thienyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanol,

[0099] 5-(3-chlorophenyl)-α-(5-chloro-2-thienyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanol,

[0100] 5-(3-chlorophenyl)-α-(3-furanyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanol,

[0101] 5-(3-chlorophenyl)-α-(3-furanyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanol,

[0102] 5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-α-(6-quinolinyl)-tetrazolo[1,5-a]quinazoline-7-methanol,

[0103] 4-(3-chlorophenyl)-6-[(5-chloro-2-thienyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1-methyl-2(1H)-quinolinone,

[0104] 5-(3-chlorophenyl)-α-(6-chloro-3-pyridinyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanol,

[0105] 5-(3-chlorophenyl)-α-(3-furanyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanamine,

[0106] 5-(3-chlorophenyl)-α-(5-chloro-2-thienyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanamine,

[0107] 5-(3-chlorophenyl)-α-(5-chloro-2-thienyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanamine,

[0108] α-(2-benzofuranyl)-5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanamine,

[0109] 5-(3-chlorophenyl)-α-(6-chloro-3-pyridinyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanamine,

[0110] 4-(3-chlorophenyl)-6-[(5-chloro-2-thienyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinazolinone,

[0111] 5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-α-(5-methyl-2-thienyl)-tetrazolo[1,5-a]quinoline-7-methanol,

[0112] 5-(3-chlorophenyl)-7-[(1-methyl-1H-imidazol-5-yl)(2-phenyl-1H-imidazol-1-yl)methyl]-tetrazolo[1,5-a]quinazoline,

[0113] α-(2-benzofuranyl)-5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanamine,

[0114] 5-(3-chlorophenyl)-7-[(2-ethyl-1H-imidazol-1-yl)(1-methyl-1H-imidazol-5-yl)methyl]-tetrazolo[1,5-a]quinazoline,

[0115] 5-(3-chlorophenyl)-α,α-bis(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanol,

[0116] 5-(3-chlorophenyl)-7-[[2-(4-fluorophenyl)-1H-imidazol-1-yl](1-methyl-1H-imidazol-5-yl)methyl]-tetrazolo[1,5-a]quinazoline,

[0117] α-benzo[b]thien-2-yl-5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanamine,

[0118] 5-(3-chlorophenyl)-7-[(1-methyl-1H-imidazol-5-yl)(2-phenyl-1H-imidazol-1-yl)-methyl]-tetrazolo[1,5-a]quinoline,

[0119] 5-(3-chlorophenyl)-7-[[2-(2-chlorophenyl)-1H-imidazol-1-yl](1-methyl-1H-imidazol-5-yl)methyl]-tetrazolo[1,5-a]quinoline,

[0120] 3-[1-[[5-(3-chlorophenyl)tetrazolo[1,5-a]quinazolin-7-yl](1-methyl-1H-imidazol-5-yl)methyl]-1H-imidazol-2-yl]-benzonitrile,

[0121] 5-(3-chlorophenyl)-7-[(2-ethyl-1H-imidazol-1-yl)(1-methyl-1H-imidazol-5-yl)methyl]-tetrazolo[1,5-a]quinoline,

[0122] and their pharmaceutically acceptable salts.

[0123] The compounds of formula (I) and their pharmaceutically acceptable salts and N-oxides and stereochemically isomeric forms thereof may be prepared in conventional manner, for example by a process which comprises:

[0124] a) cyclising a compound of formula (II)

[0125]  with a reagent serving to form a compound of formula (I) in which R⁶ is hydrogen and R⁷ is oxygen;

[0126] b) reacting a compound of formula (III):

[0127]  in which W¹ represents a replaceable or reactive group, with a reagent serving either to react with or replace the W¹ group in compound (III) to form a compound of formula (I) in which R⁶ is hydrogen and R⁷ is an oxygen or sulphur group or to react with the W¹ group and the adjacent nitrogen atom to form directly or indirectly a compound of formula (I) in which R⁶ and R⁷ together form a trivalent radical selected from formulae (x-1) to (x-10); or

[0128] c) reacting a compound of formula (IV):

[0129]  in which W² is a leaving group and W³ is the group R² above or W² is the group R⁴ above and W³ is a leaving group, with a reagent serving to replace the leaving group W² or W³ with the respective R⁴ or R² group; or

[0130] d) reacting a compound of formula (V):

[0131]  (in which R^(x) is the group R² or R⁴ above) with a heterocyclic reagent of formula R^(4a)L (when R^(x) is R²) or R^(2a)L (when R^(x) is R⁴) in which L is a leaving atom or group and R^(2a) is R² or a precursor group therefor and R^(4a) is R⁴ or a precursor group therefor, and if required, converting said precursor group to the parent group, to form a compound of formula (I) in which R³ is hydroxy;

[0132] e) reacting a compound of formula (VI):

[0133]  with a reagent serving to convert the said compound (VI) to a compound of formula (I) in which R⁶ is hydrogen and R⁷ is oxygen;

[0134] and optionally effecting one or more of the following conversions in any desired order:

[0135] (i) converting a compound of formula (I) into a different compound of formula (I);

[0136] (ii) converting a compound of formula (I) in to a pharmaceutically acceptable salt or N-oxide thereof;

[0137] (iii) converting a pharmaceutically acceptable salt or N-oxide of a compound of formula (I) into the parent compound of formula (I);

[0138] (iv) preparing a stereochemical isomeric form of a compound of formula (I) or a pharmaceutically acceptable salt or N-oxide thereof.

[0139] With regard to process a), this can be effected as described for example in an analogous manner to that described in WO 97/21701 and WO98/49157 referred to above. Thus, the cyclisation may be effected for example by subjecting the compound of formula (II) to an acetylation reaction, e.g. by treatment with the anhydride of a carboxylic acid, e.g. acetic anhydride in a reaction-inert solvent, e.g. toluene, and subsequent reaction with a base such as potassium tert-butoxide in a reaction-inert solvent such as 1,2-dimethoxyethane.

[0140] With regard to process b), this can also be effected for example in an analogous manner to that as described in WO 97/21701 and WO98/49157 referred to above for the preparation of compounds in which R⁷ is oxygen, for example by hydrolysis of an ether of formula (III) in which W¹ is C₁₋₆alkyloxy in an aqueous acid solution such hydrochloric acid. Alternatively a compound of formula (III) in which W¹ is a chloro radical can be used.

[0141] Also with regard to process b), for the preparation of compounds in which R⁶ and R⁷ together form a trivalent radical of formula (x-1) to (x-10), this can be effected as described for example in WO 00/39082 referred to above. For example, when W¹ is chloro, the compound of formula (III) can be reacted with an azide compound for example sodium azide to form a corresponding compound of formula (I) in which R⁶ and R⁷ together form a trivalent radical of formula (x-4). Alternatively, when W¹ is chloro, the compound of formula (III) can be reacted with aquous hydrazine to form a compound of formula (III) where W¹ is NHNH₂ which by reaction with sodium nitrite in acidic media form a corresponding compound of formula (I) in which R⁶ and R⁷ together form a trivalent radical of formula (x-4).

[0142] With regard to process c), this can be effected for example by N-alkylating an intermediate of formula (IVa), wherein W² is an appropriate leaving group such as, for example, chloro, bromo, methanesulfonyloxy or benzenesulfonyloxy, with an intermediate of formula (VII) to form a a compound of formula (I) in which R⁴ is a group of formula (c-1) represented by compounds of formula (I-a):

[0143] The reaction can be performed in a reaction-inert solvent such as, for example, acetonitrile, and optionally in the presence of a suitable base such as, for example, sodium carbonate, potassium carbonate or triethylamine. Stirring may enhance the rate of the reaction. The reaction may conveniently be carried out at a temperature ranging between room temperature and reflux temperature.

[0144] Also, compounds of formula (I-a) can be prepared by reacting an intermediate of formula (IVb) in which W² is hydroxy with an intermediate of formula (VIII), wherein Y is oxygen or sulfur, such as, for example, a 1,1′-carbonyldiimidazole.

[0145] Said reaction may conveniently be conducted in a reaction-inert solvent, such as, e.g. tetrahydrofuran, optionally in the presence of a base, such as sodium hydride, and at a temperature ranging between room temperature and the reflux temperature of the reaction mixture.

[0146] Similar procedures can be used to introduce the R² group using a compound of formula (IV) in which W³ is a leaving group.

[0147] With regard to process d), this can be used to introduce the R⁴ group, for example by reacting a compound of formula (V) in which R^(x) is R² with an imidazole reagent to form a compound of formula (I) in which R⁴ is a group of formula (c-2), or with a 3-mercapto-4-C₁₋₆alkyl-1,2,4-triazole reagent to form the corresponding 3-mercapto-4-C₁₋₆alkyl-1,2,4-triazole derivative, which is optionally methylated to form the corresponding 3-methylmercapto derivative, and subsequently removing the 3-mercapto or 3-methylmercapto group to form a compound of formula(I) in which R⁴ is a group of formula (c-3) in which R¹⁸ is a C₁₋₆alkyl group; or with a 3-bromopyridyl group to form a compound of formula (I) in which R⁴ is a group of formula (c-4). In more detail, the compounds of formula (I) wherein R⁴ represents a radical of formula (c-2), R³ is hydroxy and R¹⁷ is C₁₋₆alkyl, said compounds being referred to as compounds of formula (I-b-1) may be prepared by reacting an intermediate ketone of formula (Va) with an intermediate of formula (III-1). Said reaction requires the presence of a suitable strong base, such as, for example, butyl lithium in an appropriate solvent, such as, for example, tetrahydrofuran, and the presence of an appropriate silane derivative, such as, for example, triethylchlorosilane. During the work-up procedure an intermediate silane derivative is hydrolyzed. Other procedures with protective groups analogous to silane derivatives can also be applied.

[0148] Also, the compounds of formula (I), wherein R⁴ is a radical of formula (c-2), R³ is hydroxy and R¹⁷ is hydrogen, said compounds being referred to as compounds of formula (I-b-2) may be prepared by reacting an intermediate ketone of formula (Va) with a intermediate of formula (III-2), wherein PG is a protective group such as, for example, a sulfonyl group, e.g. a dimethylamino sulfonyl group, which can be removed after the addition reaction. Said reaction is conducted analogously as for the preparation of compounds of formula (I-b-1), followed by removal of the protecting group PG, yielding compounds of formula (I-b-2). Similar procedures can be used to introduce the R² group by reacting a compound of formula (V) in which R^(x) is R⁴ with a R²L reagent for example a lithium compound.

[0149] With regard to process e), this may be effected for example as described in WO 97/21701 referred to above, by reacting the nitrone of formula (VI) with the anhydride of a carboxylic acid, e.g. acetic anhydride, thus forming the corresponding ester on the 2-position of the quinoline moiety, which ester can then be hydrolysed in situ to the corresponding quinolinone using a base such potassium carbonate.

[0150] Examples of the interconversion of one compound of formula (I) into a different compound of formula (I) include the following reactions:

[0151] a) compounds of formula (I-b) can be converted to compounds of formula (I-c), defined as a compound of formula (I) wherein R⁴ is a radical of formula (c-2) and R³ is hydrogen, by submitting the compounds of formula (I-b) to appropriate reducing conditions, such as, e.g. stirring in acetic acid in the presence of formamide, or treatment with sodium borohydride/trifluoroacetic acid.

[0152] b) compounds of formula (I-b) can be converted to compounds of formula (I-f) wherein R³ is halo, by reacting the compounds of formula (I-b) with a suitable halogenating agent, such as, e.g. thionyl chloride or phosphorus tribromide. Successively, the compounds of formula (I-f) can be treated with a reagent of formula H—NR¹¹R¹² in a reaction-inert solvent, thereby yielding compounds of formula (I-g).

[0153] c) compounds of formula (I-b) can be converted into compounds of formula (I-g) for example by treatment with SOCl₂, and then NH₃/iPrOH, e.g. in a tetrahydrofuran solvent, or by treatment with acetic acid ammonium salt at a temperature ranging from 120 to 180° C., or by treatment with sulfamide at a temperature ranging from 120 to 180° C.; 2-propanone. The precipitate was filtered off and dried, yielding 0.51 g of 2-chloro-4-(3-chlorophenyl)-α-(3-furanyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinolinemethanol (intermediate 22), melting point: 246° C.

EXAMPLE A4

[0154] a) BuLi (0.13 mol) was added dropwise at −78° C. to a solution of 5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole (0.113 mol) in THF (350 ml) under N₂ flow. The mixture was stirred at −70° C. for 15 minutes. A solution of 6-quinolinecarboxaldehyde (0.124 mol) in THF (200 ml) was added dropwise. The mixture was stirred at −78° C. for 1 hour, poured out into water and extracted with CH₂Cl₂. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 100/0 to 98/2 to 0/100; 75-200 μm). Two fractions were collected and the solvent was evaporated, yielding 7 g of 5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole (starting material) and 31 g (70.9%) of α-[3-(3-chlorophenyl)-2,1-benzisoxazol-5-yl]-6-quinolinemethanol (intermediate 23).

[0155] b) MnO₂ (31 g) was added to a solution of intermediate 23 (0.08 mol) in dioxane (300 ml). The mixture was stirred and refluxed for 4 hours, cooled and filtered over celite. The solvent was evaporated. The residue was washed with 2-propanone, filtered off and dried, yielding 19.5 g (63.3%) of [3-(3-chlorophenyl)-2,1-benzisoxazol-5-yl]-6-quinolinyl-methanone (intermediate 24).

[0156] c) TiCl₃ 15% in water (20 ml) was added dropwise to a solution of intermediate 24 (0.0052 mol) in THF (20 ml). The mixture was stirred at room temperature overnight, poured out into ice water, extracted with CH₂Cl₂ and basified with K₂CO₃ 10%. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated, yielding 2 g (100%) of [4-amino-3-[1-(3-chlorobenzoyl)]phenyl]-6-quinolinyl-methanone (intermediate 25).

[0157] d) Trichloro-acetyl chloride (0.0062 mol) then triethylamine (0.0062 mol) were added at 5° C. to a solution of intermediate 25 (0.00517 mol) in CH₂Cl₂ (20 ml) under N₂ flow. The mixture was brought to room temperature, stirred at room temperature for 3 hours, poured out into ice water and extracted with CH₂Cl₂. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated, yielding 2.62 g (95%) of 2,2,2-trichloro-N-[2-(3-chlorobenzoyl)-4-(6-quinolinylcarbonyl)phenyl]-acetamide (intermediate 26).

[0158] e) A mixture of intermediate 26 (0.00492 mol) and ammonium acetate (0.00984 mol) in dimethylsulfoxide (25 ml) was stirred at 60° C. for 4 hours and poured out into ice water. The precipitate was filtered, taken up in acetonitrile (warm) and water, filtered and dried under a vacuum. A part (0.5 g) of this fraction (1 g, 49%) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.1; 15-40 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.2 g of 4-(3-chlorophenyl)-6-(6-quinolinylcarbonyl)-2(1H)-quinazolinone (intermediate 27), melting point: >260° C.

[0159] f) A mixture of intermediate 27 (0.0325 mol) in phosphoryl chloride (80 ml) was stirred at 100° C. for 2 hours, then cooled and the solvent was evaporated. The residue was taken up in CH₂Cl₂, poured out into ice water, basified with K₂CO₃ 10% and extracted with CH₂Cl₂. The organic layer was washed with water, dried (MgSO₄), separated, dried (MgSO₄), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 85/1; 15-35 μm). The pure fractions were collected and the solvent was evaporated, yielding 1 g of [2-chloro-4-(3-chlorophenyl)-6-quinazolinyl]-6-quinolinyl-methanone (intermediate 28), melting point: 170° C.

[0160] g) BuLi (0.0345 mol) was added dropwise at −70° C. to a solution of 1-methyl-1H-imidazole (0.0345 mol) in THF (30 ml) under N₂ flow. The mixture was stirred for 15 minutes. Chlorotriethyl-silane (0.0354 mol) was added dropwise. The mixture was stirred at −70° C. for 15 minutes. BuLi (0.0305 mol) was added dropwise. The mixture was stirred for 15 minutes. A solution of intermediate 28 (0.0197 mol) in THF (85 ml) was added dropwise at −70° C. The mixture was stirred at −70° C. for 1 hour, poured out into water, extracted with CH₂Cl₂ and washed with water. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.1; 15-35 μm). The fractions were collected and the solvent was evaporated. Yielding: 5.2 g (51%). A sample (2.9 g) was crystallized from 2-propanone. The precipitate was filtered off and dried, yielding 2.03 g of 2-chloro-4-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-α-(6-quinolinyl)-6-quinazolinemethanol (intermediate 29), melting point 250° C.

EXAMPLE A5

[0161] a) BuLi (0.044 mol) was added dropwise at −70° C. to a solution of 5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole (0.044 mol) in THF (130 ml) under N₂ flow. The mixture was stirred at −70° C. for 15 minutes. A solution of (6-chloro-3-pyridinyl)(1-methyl-1H-imidazol-5-yl)-methanone (0.028 mol) in THF (80 ml) was added dropwise. The mixture was stirred at −70° C. for 1.5 hour, then poured out into water and extracted with CH₂Cl₂. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.1; 15-35 μm). The fractions were collected and the solvent was evaporated. Yielding: 2.5 g (21%). A sample (0.9 g) was crystallized from CH₃CN/diethyl ether. The precipitate was filtered off and dried, yielding 0.85 g of 3-(3-chlorophenyl)-α-(6-chloro-3-pyridinyl)-α-(1-methyl-1H-imidazol-5-yl)-2,1-benzisoxazole-5-methanol (intermediate 30), melting point 230° C.

[0162] b) TiCl₃ 15% in water (23 ml) was added dropwise at 5° C. to a mixture of intermediate 30) (0.0005 mol) in THF (23 ml). The mixture was stirred at 5° C. for 5 hours, poured out into ice water, basified with NaOH 3N and filtered over celite. The organic layer was washed with water, separated, dried (MgSO₄), filtered and the solvent was evaporated, yielding 1.5 g (66%) of [2-amino-5-[(6-chloro-3-pyridinyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]phenyl](3-chlorophenyl)-methanone (intermediate 31).

[0163] c) Trichloro-acetyl chloride (0.003 mol) then triethylamine (0.003 mol) were added dropwise at 5° C. to a mixture of intermediate 31 (0.003 mol) in dichloromethane (15 ml) under N₂ flow. The mixture was stirred at room temperature for 5 hours, poured out into ice water and extracted with CH₂Cl₂. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated, yielding 1.97 g (100%) of 2,2,2-trichloro-N-[2-(3-chlorobenzoyl)-4-[(6-chloro-3-pyridinyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]phenyl]-acetamide (intermediate 32).

EXAMPLE A6

[0164] a) Trichloro-acetyl chloride (0.224 mol) was added dropwise at 5° C. to a mixture of (2-amino-5-bromophenyl)(3-chlorophenyl)-methanone (0.187 mol) in dichloromethane (520 ml). The mixture was stirred for 20 minutes. Triethylamine (0.224 mol) was added dropwise. The mixture was stirred at room temperature for 1 hour and 30 minutes, poured out into ice water and extracted with EtOAc. The organic layer was separated, washed with water, dried (MgSO₄), filtered and the solvent was evaporated, yielding 81 g (95%) of N-[4-bromo-2-(3-chlorobenzoyl)phenyl]-2,2,2-trichloro-acetamide (intermediate 33). The product was used without further purification in the next reaction step.

[0165] b) A mixture of intermediate 33 (0.160 mol) and acetic acid, ammonium salt (0.320 mol) in dimethylsulfoxide (500 ml) was stirred at 120° C. for 1 hour then cooled and poured out into ice water. The precipitate was filtered, washed with water (4 liters) then with acetonitrile and dried, yielding 42 g (79%). A part (1 g) of the residue (84 g, 79%) was crystallized from CH₃CN/CH₃OH. The precipitate was filtered off and dried, yielding 0.43 g of 6-bromo-4-(3-chlorophenyl)-2(1H)-quinazolinone (intermediate 34), melting point 281° C.

[0166] c) A mixture of intermediate 34 (0.06 mol) in phosphoryl chloride (100 ml) was stirred and refluxed for 1 hour and 30 minutes then cooled. The solvent was evaporated. The residue was taken up several times in CH₂Cl₂. The solvent was evaporated, yielding 24 g (quantitative) of 6-bromo-2-chloro-4-(3-chlorophenyl)-quinazoline (intermediate 35). The product was used without further purification in the next reaction step.

[0167] d) CH₃OH (200 ml) was added slowly at 5° C. to intermediate 35 (0.06 mol). The mixture was stirred at 5° C. for 15 minutes. CH₃ONa/CH₃OH (0.36 mol) was added dropwise slowly at 5° C. then brought to room temperature, stirred and refluxed for 1 hour, cooled, poured out into ice water and extracted with CH₂Cl₂. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated. The residue (21 g) was crystallized from DIPE. The precipitate was filtered off and dried, yielding 17.7 g (84%) of 6-bromo-4-(3-chlorophenyl)-2-methoxy-quinoline (intermediate 36), melting point 132° C.

[0168] e) A mixture of intermediate 36 (0.0315 mol), Pd(PPh₃)₄ (0.00315 mol) and N-methoxy-methanamine (0.069 mol) in triethylamine (22 ml) and dioxane (100 ml) was stirred at 100° C. for 18 hours under a 5 bar pressure of CO, then cooled, poured out into ice water, extracted with CH₂Cl₂ and filtered over celite. The organic layer was separated, dried (MgSO₄), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH₂Cl₂/EtOAc 85/15 then CH₂Cl₂/CH₃OH/NH₄OH 98/2/0.4; 15-35 μm). The fractions were collected and the solvent was evaporated, yielding 3 g (27%) of 4-(3-chlorophenyl)-N,2-dimethoxy-N-methyl-6-quinazolinecarboxamide (intermediate 37), melting point: 118° C.

[0169] f) Phosphoryl chloride (0.084 mol) was added dropwise at room temperature to a solution of intermediate 37 (0.042 mol) in DMF (110 ml). The mixture was stirred at 80° C. for 4 hours, cooled, poured out into ice water, extracted with EtOAc and basified with K₂CO₃ solid. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated. The residue was crystallised from DMF. The precipitate was filtered off and dried. Part (0.15 g) of the residue (9 g/59%) was dried at 90° C. under a vacuum, yielding 0.12 g of 2-chloro-4-(3-chlorophenyl)-N-methoxy-N-methyl-6-quinazolinecarboxamide (intermediate 38), melting point 110° C.

[0170] g) BuLi 1.6M in hexane (0.042 mol, 26.2 ml) was added dropwise at −70° C. to a mixture of 1-methyl-1H-imidazole (0.042 mol) in THF (80 ml) under N₂ flow. The mixture was stirred for 15 minutes. Chlorotriethyl-silane (0.043 mol) was added. The mixture was stirred for 15 minutes. BuLi 1.6M in hexane (0.037 mol, 23.2 ml) was added at −70° C. The mixture was stirred for 15 minutes. A solution of intermediate 38 (0.024 mol) in THF (80 ml) was added at −70° C. The mixture was stirred at −70° C. for 30 minutes, poured out into water and extracted with EtOAc. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated. The residue (13 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 97/3; 15-35 μm). Two fractions were collected and the solvent was evaporated, yielding 1.4 g F1 and 2.4 g F2 Each fraction was purified by column chromatography over silica gel (eluent: CH₂Cl₂/EtOAc 50/50 then CH₂Cl₂/CH₃OH 97/3; 15-40 μm). The fractions were collected and the solvent was evaporated, yielding 2.46 g (27%) of [2-chloro-4-(3-chlorophenyl)-6-quinazolinyl](1-methyl-1H-imidazol-5-yl)-methanone (intermediate 39), melting point: 190° C.

[0171] h) A toluene solution (20%) of Hydrobis (2-methylpropyl)-aluminum (10 ml) was added dropwise at −70° C. to a mixture of intermediate 39 (0.012 mol) in THF (150 ml) under N₂ flow. The mixture was stirred at −70° C. for 30 minutes. Hydrobis(2-methylpropyl)-aluminum (50 ml) was added. The mixture was stirred at −70° C. for 3 hours, poured out into ice water, extracted with CH₂Cl₂ and filtered over celite. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated, yielding 4 g (86%) of 2-chloro-4-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol (intermediate 40), melting point 140° C.

[0172] i) NaN₃ (0.031 mol) was added at room temperature to a mixture of intermediate 40 (0.0103 mol) in DMF (40 ml). The mixture was stirred at 90° C. for 4 hours, then cooled, poured out into ice water and stirred at room temperature for 1 hour. The precipitate was filtered off and dried at 80° C. under a vacuum, yielding 3.4 g (84%) of 5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanol (intermediate 41), melting point 190° C.

[0173] j) A mixture of intermediate 41 (0.0025 mol) in thionyl chloride (10 ml) was stirred at 65° C. for 4 hours, then cooled and the solvent was evaporated till dryness. The residue was taken up twice in CH₂Cl₂. The solvent was evaporated till dryness, yielding 7-[chloro(1-methyl-1H-imidazol-5-yl)methyl]-5-(3-chlorophenyl)-tetrazolo[1,5-a]quinazoline as a hydrochloride salt (intermediate 42).

B. PREPARATION OF THE FINAL COMPOUNDS EXAMPLE B1

[0174] A mixture of intermediate 8 (0.0040 mol) and sodium azide (0.0119 mol) in DMF (40 ml) was stirred at 90° C. for 3 hours, cooled and poured out into ice water. The precipitate was filtered. The filtrate was extracted with CH₂Cl₂. The organic layer was brought together with the precipitate dissolved in CH₂Cl₂. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated. The residue was crystallized from CH₃CN/DIPE. The precipitate was filtered off and dried, yielding 1.33 g (66%) of 5-(3-chlorophenyl)-α-(5-chloro-2-thienyl)-α-(1-methyl-1H-imidazol-5-yl)-)tetrazolo[1,5-a]quinazoline-7-methanol (compound 1), melting point: 202° C.

EXAMPLE B2

[0175] Sodium nitrite (0.00025 mol) was added at 5° C. to a mixture of nitric acid (0.5 ml) in water (0.5 ml). A solution of intermediate 19 (0.00025 mol) in THF (1.5 ml) was added dropwise at 5° C. The mixture was stirred at 5° C. for 30 minutes, poured out into ice water, basified with K₂CO₃ 10% and extracted with EtOAc. The organic layer was washed with H₂O, separated, dried (MgSO₄), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 100/0 to 90/10; 10 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.04 g (33%) of 4-(3-chlorophenyl)-6-[(5-chloro-2-thienyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1-methyl-2(1H)-quinolinone (compound 2) MS (MH⁺):496, 498, 500.

EXAMPLE B3

[0176] a) A mixture of intermediate 22 (0.0022 mol) and NaN₃ (0.0066 mol) in DMF (10 ml) was stirred at 140° C. for 3 hours, cooled, poured out into water and stirred. The precipitate was filtered, washed with water, then with diethyl ether and dried. The residue (0.94 g, 93%) was crystallized from 2-propanone. The precipitate was filtered off and dried, yielding 0.75 g (74%) of 5-(3-chlorophenyl)-α-(3-furanyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanol (compound 3), melting point: 188° C.

[0177] b) Compound 3 (0.00131 mol) was added at 5° C. in thionyl chloride (6 ml). The mixture was stirred at room temperature for 2 hours. Thionyl chloride was evaporated. The residue was taken up in CH₂Cl₂. The solvent was evaporated till dryness, yielding (100%) of 7-[chloro-3-furanyl(1-methyl-1H-imidazol-5-yl)methyl]-5-(3-chlorophenyl)-tetrazolo[1,5-a]quinoline (compound 4). The product was used without further purification.

[0178] c) NH₃/iPrOH (6 ml) was added dropwise at 5° C. to a solution of compound 4 (0.00131 mol) in THF (6 ml). The mixture was stirred at room temperature for 3 hours, poured out into water and extracted with EtOAc. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated. The residue (0.6 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.5; 15-40 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.2 g (33%) of 5-(3-chlorophenyl)-α-(3-furanyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanamine (compound 5) MS (MH⁺):455, 457.

EXAMPLE B4

[0179] a) A mixture of intermediate 29 (0.005 mol) in HCl 6N (50 ml) was stirred and refluxed for 18 hours, then cooled. The solvent was evaporated. The residue was taken up in a minimum of water, basified with K₂CO₃. The precipitate was filtered, washed with water and dried under a vacuo, yielding 2.5 g (100%) of 4-(3-chlorophenyl)-6-[hydroxy(1-methyl-1H-imidazol-5-yl)-6-quinolinylmethyl]-2(1H)-quinazolinone (compound 6).

[0180] b) A solution of BTEAC (0.0005 mol) in NaOH (25 ml) then iodomethane (0.006 mol) were added dropwise to a mixture of compound 6 (0.005 mol) in THF (25 ml). The mixture was stirred at room temperature for 24 hours, then poured out into water and extracted with CH₂Cl₂. The organic layer was separated, dried (MgSO₄), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 93/7/0.5; 15-40 μm). The fractions were collected and the solvent was evaporated, yielding: 0.656 g (26%) of 4-(3-chlorophenyl)-6-[hydroxy(1-methyl-1H-imidazol-5-yl)-6-quinolinylmethyl]-1-methyl-2(1H)-quinazolinone (compound 7), melting point: 192° C.

EXAMPLE B5

[0181] A mixture of intermediate 8 (0.0007 mol) in HCl 3N (5 ml) was stirred and refluxed for 30 minutes. The solvent was evaporated. The residue was taken up in a minimum of water, basified with K₂CO₃, filtered, rinsed with water and dried. The residue was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 90/10/0.2 to 50/50/1; 15-40 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.323 g (83.8%) of 4-(3-chlorophenyl)-6-[(5-chloro-2-thienyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-2(1H)-quinazolinone (compound 8) MS (MH⁺):482, 484, 486.

EXAMPLE B6

[0182] Ammonium acetate (0.006 mol) was added to a mixture of intermediate 32 (0.003 mol) in dimethylsulfoxide (20 ml). The mixture was stirred at 60° C. for 4 hours, then cooled, poured out into ice water and filtered. The precipitate was taken up in CH₂Cl₂/toluene, filtered off and dried under a vacuo, yielding 0.66 g (42%) of 4-(3-chlorophenyl)-6-[(6-chloro-3-pyridinyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-2(1H)-quinazolinone (compound 9) MS (MH⁺):477, 479, 481.

EXAMPLE B7

[0183]2-Phenyl-1H-imidazole (0.0038 mol) was added at room temperature to a mixture of intermediate 42 (0.0025 mol) in acetonitrile (10 ml). The mixture was stirred and refluxed for 2 hours, poured out into ice water and extracted with CH₂Cl₂/CH₃OH. The organic layer was washed with K₂CO₃, separated, dried (MgSO₄), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 96/4/0.2; 15-40 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.2 g) was dried at 80° C. for 3 hours, yielding 0.17 g (13%) of, 5-(3-chlorophenyl)-7-[(1-methyl-1H-imidazol-5-yl)(2-phenyl-1H-imidazol-1-yl)methyl]-tetrazolo[1,5-a]quinazoline (compound 10), melting point: 150° C.

[0184] Table F-1 lists the compounds that were prepared according to one of the above Examples. The following abbreviations were used in the tables: TABLE F-1

Co. No. 11; Ex. B1; mp. 232° C.

Co. No. 12; Ex. B1; mp. 188° C.

Co. No. 13; Ex. B1; mp. 228° C.

Co. No. 14; Ex. B1; mp. 200° C.

Co. No. 15; Ex. B1; mp. 245° C.

Co. No. 16; Ex. B1; mp. 192° C.

Co. No. 17; Ex. B3; mp. 220° C.

Co. No. 18; Ex. B3; MS (MH⁺): 505, 507

Co. No. 19; Ex. B3; MS (MH⁺): 500, 502 504

Co. No. 20; Ex. B4; mp. 160° C.

Co. No. 21; Ex. B1; mp. 210

Co. No. 22; Ex. B1; mp. 218° C.

Co. No. 23; Ex. B1; mp. 242° C.

Co. No. 24; Ex. B1; mp. 192° C.

Co. No. 25; Ex. B1; mp. 190° C.

Co. No. 26; Ex. B1; mp. 200° C.

Co. No. 27; Ex. B3; MS (MH⁺): 506, 508

Co. No. 28; Ex. B7; mp. 120° C.

Co. No. 29; Ex. B1; mp. 220° C.

Co. No. 30; Ex. B7; mp. 154° C.

Co. No. 31; Ex. B3; mp. 254° C.

Co. No. 32; Ex. B7; mp. 148° C.

Co. No. 33; Ex. B1; mp. 178° C.

Co. No. 34; Ex. B7; mp. 177° C.

Co. No. 35; Ex. B7; MS (MH⁺): 542, 544

Co. No. 36; Ex. B7; MS (MH⁺): 468, 470

Co. No. 37; Ex. B3; mp. 208° C.

C. PHARMACOLOGICAL EXAMPLE EXAMPLE C.1

[0185] “In Vitro Assay for Inhibition of Farnesyl Protein Transferase”:

[0186] An in vitro assay for inhibition of farnesyl transferase was performed essentially as described in WO 98/40383, pages 33-34.

EXAMPLE C.2

[0187] “Ras-Transformed Cell Phenotype Reversion Assay”.

[0188] The ras-transformed cell phenotype reversion assay was performed essentially as described in WO 98/40383, pages 34-36.

EXAMPLE C.3

[0189] “Farnesyl Protein Transferase Inhibitor Secondary Tumor Model”.

[0190] The farnesyl protein transferase inhibitor secondary tumor model was used as described in WO 98/40383, page 37.

D. COMPOSITION EXAMPLE

[0191] Film-Coated Tablets

[0192] Preparation of Tablet Core

[0193] A mixture of 100 g of a compound of formula (I), 570 g lactose and 200 g starch is mixed well and thereafter humidified with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinyl-pyrrolidone in about 200 ml of water. The wet powder mixture is sieved, dried and sieved again. Then there are added 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. The whole is mixed well and compressed into tablets, giving 10.000 tablets, each comprising 10 mg of a compound of formula (I).

[0194] Coating

[0195] To a solution of 10 g methyl cellulose in 75 ml of denaturated ethanol there is added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane. Then there are added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycol is molten and dissolved in 75 ml of dichloromethane. The latter solution is added to the former and then there are added 2.5 g of magnesium octadecanoate, 5 g of polyvinyl-pyrrolidone and 30 ml of concentrated colour suspension and the whole is homogenated. The tablet cores are coated with the thus obtained mixture in a coating apparatus. 

1. A compound of formula (I):

or a pharmaceutically acceptable salt or N-oxide or stereochemically isomeric form thereof, wherein r is 0, 1, 2, 3, 4 or 5; t is 0, 1, 2 or 3; >Y¹-Y²—is a trivalent radical of formula >C═N— (y-1) >C═CR⁹— (y-2) >CH—NR⁹— (y-3) >CH—CHR⁹— (y-4)

wherein R⁹ is hydrogen, halo, cyano, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkyloxy, halocarbonyl, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, aryl or a group of formula —NR²²R²³, —C₁₋₆alkyl-NR²²R²³, —C₂₋₆alkenyl-NR²²R²³, —CONR²²R²³ or —NR²²—C₁₋₆alkyl-NR²²R²³; p is 0 to 5; R²⁰ and R²¹ are independently hydrogen or C₁₋₆ alkyl and are independently defined for each iteration of p in excess of 1; R²² and R²³ are independently hydrogen, C₁₋₆ alkyl or —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, or together with the adjacent nitrogen atom form a 5- or 6-membered heterocyclic ring optionally containing one, two or three further heteroatoms selected from oxygen, nitrogen or sulphur and optionally substituted by one or two substituents each independently selected from halo, hydroxy, cyano, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, aminocarbonyl, mono- or di-(C₁₋₆alkyl)aminocarbonyl, amino, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkylsulfonylamino, oxime, or phenyl; R¹ is azido, hydroxy, halo, cyano, nitro, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, hydroxycarbonylC₁₋₆alkyloxyC₁₋₆alkyl, R²⁴SC₁₋₆alkyl, trihalomethyl, arylC₁₋₆alkyl, Het²C₁₋₆alkyl, —C₁₋₆alkyl-NR²²R²³, —C₁₋₆alkylNR²²C₁₋₆alkylNR²²R²³, —C₁₋₆alkylNR²²COC₁₋₆alkyl, —C₁₋₆alkylNR²²COAlkAr², —C₁₋₆alkylNR²²COAr², C₁₋₆alkylsulphonylaminoC₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, —OC₁₋₆alkyl-NR²²R²³, trihalomethoxy, arylC₁₋₆alkyloxy, Het²C₁₋₆alkyloxy, C₁₋₆alkylthio, C₂₋₆alkenyl, cyanoC₂₋₆alkenyl, —C₂₋₆alkenyl-NR²²R²³, hydroxycarbonylC₂₋₆alkenyl, C₁₋₆alkyloxycarbonylC₂₋₆alkenyl, C₂₋₆alkynyl, —CHO, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkylcarbonyl, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR²²R²³, —CONR²²—C₁₋₆alkyl-NR²²R²³, —CONR²²—C₁₋₆alkyl-Het², —CONR²²—C₁₋₆alkyl-Ar², —CONR²²—O—C₁₋₆alkyl, —CONR²²—C₁₋₆alkenyl, —NR²²R²³, —OC(O)R²⁴, —CR²⁴═NR²⁵, —CR²⁴═N—OR²⁵, —NR²⁴C(O) NR²²R²³, —NR²⁴SO₂R²⁵, —NR²⁴C(O)R²⁵, —S(O)₀₋₂R²⁴, —SO₂NR²⁴R²⁵, —C(NR²⁶R²⁷)═NR²⁸; —Sn(R²⁴)₃, —SiR²⁴R²⁴R²⁵, —B(OR²⁴)₂, —P(O)OR²⁴OR²⁵, aryloxy, Het²-oxy, or a group of formula —Z, —CO—Z or —CO—NR^(y)—Zin which R^(y) is hydrogen or C₁₋₄alkyl and Z is phenyl or a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from oxygen, sulphur and nitrogen, the phenyl or heterocyclic ring being optionally substituted by one or two substituents each independently selected from halo, cyano, hydroxycarbonyl, aminocarbonyl, C₁₋₆alkylthio, hydroxy, —NR²²R²³, C₁₋₆alkylsulphonylamino, C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkyloxy or phenyl; or two R¹ substituents adjacent to one another on the phenyl ring may form together a bivalent radical of formula —O—CH₂—O— (a-1) —O—CH₂—CH₂—O— (a-2) —O—CH═CH— (a-3) —O—CH₂—CH₂— (a-4) —O—CH₂—CH₂—CH₂— (a-5) —CH═CH—CH═CH— (a-6)

R²⁴ and R²⁵are independently hydrogen, C₁₋₆ alkyl, —(CR₂₀R₂₁)p-C₃₋₁₀cycloalkyl or arylC₁₋₆alkyl; R²⁶, R²⁷ and R²⁸ are independently hydrogen and C₁₋₆alkyl or C(O) C₁₋₆alkyl; R² is a mono- or bi-cyclic heterocyclic ring containing one or more heteroatoms selected from oxygen, sulphur and nitrogen and optionally substituted by one or two substituents each independently selected from halo, cyano, hydroxy, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR²²R²³, C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR²²R²³, —NR²²R²³, C₁₋₆alkylsulfonylamino, oxime, phenyl or benzyl; R³ is hydrogen, halo, cyano, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, haloC₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, arylC₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkylthioC₁₋₆alkyl, hydroxycarbonylC₁₋₆alkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, —C₁₋₆alkyl-NR²²R²³, —C₁₋₆alkyl-CONR²²R²³, arylC₁₋₆alkyl, Het²C₁₋₆alkyl, C₂₋₆alkenyl, —C₂₋₆alkenyl NR²²R²³, C₂₋₆alkynyl, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, aryl, or Het²; or a radical of formula —O—R¹⁰ (b-1) —S—R¹⁰ (b-2) —NR¹¹R¹² (b-3) or —N═C R^(10′)R¹¹ (b-4)

wherein R¹⁰ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, arylC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkylcarbonyl, aryl, a group of formula —NR²²R²³R or —C₁₋₆alkylC(O)OC₁₋₆alkyl NR²²R²³, or a radical of formula -Alk-OR¹³ or -Alk-NR¹⁴R¹⁵; R^(10′) is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, arylC₁₋₆alkyl, aryl or a group of formula —NR²²R²³; R¹¹ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl or arylC₁₋₆alkyl; R¹² is hydrogen, hydroxy, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl, arylC₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, C₁₋₆alkyloxy, a group of formula —NR²²R²³, C₁₋₆alkylcarbonylamino, C₁₋₆alkylcarbonyl, haloC₁₋₆alkylcarbonyl, arylC₁₋₆alkylcarbonyl, Het²C₁₋₆alkylcarbonyl, arylcarbonyl, C₁₋₆alkyloxycarbonyl, trihalo C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, aminocarbonyl, mono- or di(C₁₋₆alkyl)aminocarbonyl wherein the alkyl moiety may optionally be substituted by one or more substituents independently selected from aryl andC₁₋₆alkyloxycarbonyl substiuents; aminocarbonylcarbonyl, mono- ordi(C₁₋di(C₁₋₆alkyl)amino-C₁₋₆alkylcarbonyl, or a radical of formula -Alk-OR¹³ or Alk-NR¹⁴R¹⁵; wherein Alk is C₁₋₆alkanediyl; R¹³ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkyl, aryl or arylC₁₋₆alkyl; R¹⁴ is hydrogen,C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl or arylC₁₋₆alkyl; R¹⁵ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkylcarbonyl, aryl or arylC₁₋₆alkyl; R⁴ is a radical of formula

wherein R¹⁶ is hydrogen, halo, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkylS(O)₀₋₂C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, a group of formula —NR²²R²³, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl or aryl, R¹⁷ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aryl C₁₋₆alkyl, trifluoromethyl, trifluoromethylC₁₋₆alkyl, hydroxycarbonylC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, mono- or di (C₁₋₆alkyl)aminosulphonyl or —C₁₋₆alkylP(O)OR²⁴OR²⁵; R¹⁸ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, arylC₁₋₆alkyl or C₁₋₆alkyloxyC₁₋₆alkyl; R^(18a) is hydrogen, —SH or —SC₁₋₄alkyl; R⁵ is cyano, hydroxy, halo, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkyloxy, arylC₁₋₆alkyloxy, Het²C₁₋₆alkyloxy, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, or a group of formula —NR²²R²³ or —CONR²²R²³; R⁶ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, cyanoC₁₋₆alkyl, —C₁₋₆alkylCO₂R²⁴, aminocarbonylC₁₋₆alkyl or —C₁₋₆alkyl-NR²²R²³, R²⁴SO₂, R²⁴SO₂C₁₋₆alkyl, —C₁₋₆alkyl-OR²⁴, —C₁₋₆alkyl-SR²⁴, —C₁₋₆alkylCONR²²—C₁₋₆alkyl-NR²²R²³, —C₁₋₆alkylCONR²²—C₁₋₆alkyl-Het², —C₁₋₆alkylCONR²²—C₁₋ ₆alkyl-Ar², —C₁₋₆alkyl CONR²²-Het², —C₁₋₆alkylCONR²²Ar², —C₁₋₆alkylCONR²²—O—C₁₋₆alkyl, —C₁₋₆alkylCONR²²—C₁₋₆alkenyl, -Alk-Ar² or -AlkHet²; R⁷ is oxygen or sulphur; or R⁶ and R⁷ together form a trivalent radical of formula: —CR³⁰═CR³¹—N═ (x-1) —CR³⁰═CR³¹—CR³²═ (x-6) —CR³⁰═N—N═ (x-2) —CR³⁰═N—CR³¹═ (x-7) —C(═O)—NH—N═ (x-3) —C(═O)═NH═CR³⁰═ (x-8) —N═N—N═ (x-4) —N═N—CR³⁰═ (x-9) or —N═CR³⁰—N═ (x-5) —CH₂—(CH₂)₀₋₁—CH₂—N═ (x-10)

wherein each R³⁰, R³¹ and R³² are independently hydrogen, C₁₋₆ alkyl, —OR²⁴, —COOR²⁴, —NR²²R²³, —C₁₋₆ alkylOR²⁴, —C₁₋₆ alkylSR²⁴, R²³R²²NC₁₋₆alkyl-, —CONR²²R²³, C₂₋₆alkenyl, C₂₋₆alkenylAr², C₂₋₆alkenylHet², cyano, amino, thio, C₁₋₆ alkylthio, —O—Ar², —S—Ar² or Ar²; Ar² is phenyl, naphthyl or phenyl or naphthyl substituted by one to five substituents each independently selected from halo, hydroxy, cyano, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR²²R²³, C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, aryloxy, —NR²²R²³, C₁₋₆alkylsulfonylamino, oxime or phenyl, or a bivalent substituent of formula —O—CH₂—O— or —O—CH₂—CH₂—O—; Het² is a mono- or bi-cyclic heterocyclic ring containing one or more heteroatoms selected from oxygen, sulphur and nitrogen and optionally substituted by one or two substituents each independently selected from halo, hydroxy, cyano, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR²²R²³, C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR²²R²³, —NR²²R²³, C₁₋₆alkylsulfonylamino, oxime or phenyl; provided that when >Y¹-Y² is a radical of formula (y-2) or (y-4) and (a) R⁴ is a radical of formula (c-1), (c-2) or (c-4) and/or (b) R² is an optionally substituted imidazolyl or pyridyl group, then R⁷ is not oxygen or sulphur.
 2. A compound according to claim 1 in which: r is 0, 1 or 2; t is 0 or 1; >Y¹-Y²—is a trivalent radical of formula >C═N—  (y-1)>C═CR⁹—  (y-2)wherein R⁹ is hydrogen, cyano, halo, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, hydroxycarbonyl or aminocarbonyl; R¹ is halo, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, trihalomethyl, trihalomethoxy, C₂₋₆alkenyl, hydroxycarbonylC₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, aminoC₁₋₆alkyloxy, C₁₋₆alkylthio, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR²²R²³, or —CH═NOR²⁵; or two R¹ substituents adjacent to one another on the phenyl ring may independently form together a bivalent radical of formula —O—CH₂—O— (a-1) —O—CH₂—CH₂—O— (a-2)

R² is a 5- or 6-membered monocyclic heterocyclic ring containing one, two or three heteroatoms selected from oxygen, sulphur or nitrogen or a 9- or 10-membered bicyclic heterocyclic ring R³ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, haloC₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, —C₁₋₆alkyl NR²²R²³, Het²C₁₋₆alkyl, —C ₂₋₆alkenyl NR²²R²³, or -Het²; or a group of formula —O—R¹⁰ (b-1) —NR¹¹R¹² (b-3)

wherein R¹⁰ is hydrogen, C₁₋₆alkyl, or —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, or a group of formula -Alk-OR¹³ or -Alk-NR¹⁴R¹⁵; R¹¹ is hydrogen or C₁₋₆alkyl; R¹² is hydrogen, hydroxy, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, aminocarbonyl, or a radical of formula -Alk-OR¹³ or Alk-NR¹⁴R¹⁵; wherein Alk is C₁₋₆alkanediyl; R¹³ is hydrogen, C₁₋₆alkyl or —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl; R¹⁴ is hydrogen, C₁₋₆alkyl, or —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl; R¹⁵ is hydrogen or C₁₋₆alkyl; R⁴ is a radical of formula (c-2) or (c-3) wherein R¹⁶ is hydrogen, halo or C₁₋₆alkyl, R¹⁷ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₁₋₆alkyloxyC₁₋₆alkyl or trifluoromethyl; R¹⁸ is hydrogen, C₁₋₆alkyl or —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl; R^(18a) is hydrogen; R⁵ is cyano, halo, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkyloxy or C₁₋₆alkyloxycarbonyl: R⁶ is hydrogen, C₁₋₆alkyl, —C₁₋₆alkylCO₂R²⁴, —C₁₋₆alkyl-C(O)NR²²R²³, -Alk-Ar², -AlkHet² or —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, R⁷ is oxygen; or R⁶ and R⁷ together form a trivalent radical of formula (x-1), (x-2), (x-3), (x-4) or (x-9) Het² is a 5- or 6-membered monocyclic heterocyclic ring containing one, two or three heteroatoms selected from oxygen, sulphur or nitrogen for example pyrrolidinyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, furyl, morpholinyl, piperazinyl, piperidinyl, thiophenyl, thiazolyl or oxazolyl, or a 9- or 10-membered bicyclic heterocyclic ring especially one in which a benzene ring is fused to a heterocyclic ring containing one, two or three heteroatoms selected from oxygen, sulphur or nitrogen for example indolyl, benzofuryl, benzothienyl, quinolinyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzothiazolyl or benzodioxolanyl.
 3. A compound according to claim 1 in which: >Y¹-Y²—is a trivalent radical of formula (y-1) or (y-2), wherein R⁹ is hydrogen, halo, C₁₋₄alkyl, hydroxycarbonyl, or C₁₋₄alkyloxycarbonyl; r is 0, 1 or 2; t is 0; R¹ is halo, C₁₋₆alkyl or two R¹ substituents ortho to one another on the phenyl ring may independently form together a bivalent radical of formula (a-1); R² is a 5- or 6-membered monocyclic heterocyclic ring containing one or two heteroatoms selected from oxygen, sulphur or nitrogen or a 9- or 10-membered bicyclic heterocyclic ring in which a benzene ring is fused to a heterocyclic ring containing one, two or three heteroatoms selected from oxygen, sulphur or nitrogen, optionally substituted by halo, cyano, C₁₋₆alkyl or aryl; R³ is Het² or a group of formula (b-1) or (b-3) wherein R¹⁰ is hydrogen or a group of formula -Alk-OR¹³. R¹¹ is hydrogen; R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxy, C₁₋₆alkyloxy or mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl; Alk is C₁₋₆alkanediyl and R¹³ is hydrogen; R⁴ is a group of formula (c-2) or (c-3) wherein R¹⁶ is hydrogen, halo or mono- or di(C₁₋₄alkyl)amino; R¹⁷ is hydrogen or C₁₋₆alkyl; R¹⁸ is hydrogen or C₁₋₆alkyl; R^(18a) is hydrogen; R⁶ is —(CR²⁰R²¹)p-C₃₋₁₀cycloalkyl, —C₁₋₆alkylCO₂R²⁴, aminocarbonylC₁₋₆alkyl, -Alk-Ar² or -AlkHet² or C₁₋₆alkyl; R⁷ is oxygen; or R⁶ and R⁷ together form a trivalent radical of formula (x-1), (x-2), (x-3), (x-4) or (x-9); aryl is phenyl.
 4. A compound according to claim 1 in which: >Y¹-Y² is a trivalent radical of formula (y-1) or (y-2), r is 0 or 1, t is 0, R¹ is halo, C₍₁₋₄₎alkyl or forms a bivalent radical of formula (a-1), R² is a 5- or 6-membered monocyclic heterocyclic ring containing one or two heteroatoms selected from oxygen, sulphur or nitrogen or a 9- or 10-membered bicyclic heterocyclic ring in which a benzene ring is fused to a heterocyclic ring containing one or two heteroatoms selected from oxygen, sulphur or nitrogen, optionally substituted by halo, cyano, C₁₋₆alkyl or aryl; R³ is hydrogen or a radical of formula (b-1) or (b-3), R¹⁰ is hydrogen or -Alk-OR¹³, R¹¹ is hydrogen and R¹² is hydrogen or C₁₋₆alkylcarbonyl and R¹³ is hydrogen; R⁴ is a radical of formula (c-2) or (c-3), wherein R¹⁶ is hydrogen, R¹⁷ is C₁₋₆alkyl, R¹⁸ is C₁₋₆alkyl, R^(18a) is hydrogen; R⁶ is C₁₋₆alkyl, —CH₂—C₃₋₁₀cycloalkyl, —C₁₋₆alkylCO₂R²⁴ (R²⁴═H, Et), aminocarbonylC₁₋₆alkyl, -Alk-Ar² or -AlkHet²; and R⁷ is oxygen; or R⁶ and R⁷ together form a trivalent radical of formula (x-2), (x-3) or (x-4).
 5. A compound according to claim 1 in which: >Y¹-Y² is a trivalent radical of formula (y-1) or (y-2), r is 0 or 1, s is 1, t is 0, R¹ is halo, preferably chloro and most preferably 3-chloro, R²is a thiophene, furyl, pyridyl, diazolyl, oxazolyl, benzodiazolyl, benzotriazolyl, or quinolinyl group, optionally substituted by halo preferably chloro, cyano, C₁₋₆alkyl, preferably methyl, or aryl; R³ is hydrogen or a radical of formula (b-1) or (b-3), R⁹ is hydrogen, R¹⁰ is hydrogen, R¹¹ is hydrogen and R¹² is hydrogen; R⁴ is a radical of formula (c-2) or (c-3), wherein R¹⁶ is hydrogen, R¹⁷ is C₁₋₆alkyl, R¹⁸ is C₁₋₆alkyl, R^(18a) is hydrogen; R⁶ is C₁₋₆alkyl, —CH₂—C₃₋₁₀cycloalkyl or —C₁₋₆alkylAr²; R⁷ is oxygen; or R⁶ and R⁷ together form a trivalent radical of formula (x-2) or (x-4).
 6. A compound according to claim 1 in which: >Y¹-Y² is a trivalent radical of formula (y-1) or (y-2), r is 1, t is 0, R¹ is halo, preferably chloro, and most preferably 3-chloro, R² is a 4-chloro-thiophen-2-yl, 3-furyl, 5-chloro-pyrid-3-yl, 2-phenyl-imidazol-1-yl, 2-ethyl-imidazol-1-yl, benzimidazol-1-yl or 2-hydroxy-quinoline-7-yl group; R³ is a radical of formula (b-1) or (b-3), R⁹ is hydrogen, R¹⁰ and R¹¹ are hydrogen and R¹² is hydrogen or hydroxy; R⁴ is a radical of formula (c-2) or (c-3), wherein R¹⁶ is hydrogen, R¹⁷ is C₁₋₆alkyl preferably methyl, R¹⁸ is C₁₋₆alkyl preferably methyl, R^(18a) is hydrogen; R⁶ is C₁₋₆alkyl, —CH₂—C₃₋₁₀cycloalkyl or -alkylAr²; R⁷ is oxygen; or R⁶ and R⁷ together form a trivalent radical of formula (x-4).
 7. A compounds according to claim 1 selected from: 5-(3-chlorophenyl)-α-(5-chloro-2-thienyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanol, 5-(3-chlorophenyl)-α-(5-chloro-2-thienyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanol, 5-(3-chlorophenyl)-α-(3-furanyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo-[1,5-a]quinoline-7-methanol, 5-(3-chlorophenyl)-α-(3-furanyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo-[1,5-a]quinazoline-7-methanol, 5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-α-(6-quinolinyl)-tetrazolo-[1,5-a]quinazoline-7-methanol, 4-(3-chlorophenyl)-6-[(5-chloro-2-thienyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1-methyl-2(1H)-quinolinone, 5-(3-chlorophenyl)-α-(6-chloro-3-pyridinyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanol, 5-(3-chlorophenyl)-α-(3-furanyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo-[1,5-a]quinoline-7-methanamine, 5-(3-chlorophenyl)-α-(5-chloro-2-thienyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanamine, 5-(3-chlorophenyl)-α-(5-chloro-2-thienyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanamine, α-(2-benzofuranyl)-5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanamine, 5-(3-chlorophenyl)-α-(6-chloro-3-pyridinyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanamine, 4-(3-chlorophenyl)-6-[(5-chloro-2-thienyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinazolinone, 5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-α-(5-methyl-2-thienyl)-tetrazolo[1,5-a]quinoline-7-methanol, 5-(3-chlorophenyl)-7-[(1-methyl-1H-imidazol-5-yl)(2-phenyl-1H-imidazol-1-yl)methyl]-tetrazolo[1,5-a]quinazoline, α-(2-benzofuranyl)-5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanamine, 5-(3-chlorophenyl)-7-[(2-ethyl-1H-imidazol-1-yl)(1-methyl-1H-imidazol-5-yl)methyl]-tetrazolo[1,5-a]quinazoline, 5-(3-chlorophenyl)-α,α-bis(1-methyl-1H-imidazol-5-yl)-tetrazolo-[1,5-a]quinazoline-7-methanol, 5-(3-chlorophenyl)-7-[[2-(4-fluorophenyl)-1H-imidazol-1-yl](1-methyl-1H-imidazol-5-yl)methyl]-tetrazolo[1,5-a]quinazoline, α-benzo[b]thien-2-yl-5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanamine, 5-(3-chlorophenyl)-7-[(1-methyl-1H-imidazol-5-yl)(2-phenyl-1H-imidazol-1-yl)methyl]-tetrazolo[1,5-a]quinoline, 5-(3-chlorophenyl)-7-[[2-(2-chlorophenyl)-1H-imidazol-1-yl](1-methyl-1H-imidazol-5-yl)methyl]-tetrazolo[1,5-a]quinoline, 3-[1-[[5-(3-chlorophenyl)tetrazolo[1,5-a]quinazolin-7-yl](1-methyl-1H-imidazole-5-yl)methyl]-1H-imidazol-2-yl]-benzonitrile, 5-(3-chlorophenyl)-7-[(2-ethyl-1H-imidazol-1-yl)(1-methyl-1H-imidazol-5-yl)methyl]-tetrazolo[1,5-a]quinoline, and their pharmaceutically acceptable salts.
 8. A process for preparing a compound according to claim 1 which comprises: a) cyclising a compound of formula (II)

with a reagent serving to form a compound of formula (I) in which R⁶ is hydrogen and R⁷ is oxygen; b) reacting a compound of formula (III):

in which W¹ represents a replaceable or reactive group, with a reagent serving either to react with or replace the W¹ group in compound (III) to form a compound of formula (I) in which R⁶ is hydrogen and R⁷ is an oxygen or sulphur group or to react with the W¹ group and the adjacent nitrogen atom to form directly or indirectly a compound of formula (I) in which R⁶ and R⁷ together form a trivalent radical selected from formulae (x-1) to (x-10); or c) reacting a compound of formula (IV):

in which W² is a leaving group and W³ is the group R² above or W² is the group R⁴ above and W³ is a leaving group, with a reagent serving to replace the leaving group W² or W³ with the respective R⁴ or R² group; or d) reacting a compound of formula (V):

(in which R^(x) is the group R² or R⁴ above) with a heterocyclic reagent of formula R^(4a)L (when R^(x) is R²) or R^(2a)L (when R^(x) is R⁴) in which L is a leaving atom or group and R^(2a) is R² or a precursor group therefor and R^(4a) is R⁴ or a precursor group therefor, and if required, converting said precursor group to the parent group, to form a compound of formula (I) in which R³ is hydroxy; e) reacting a compound of formula (VI):

with a reagent serving to convert the said compound (VI) to a compound of formula (I) in which R⁶ is hydrogen and R⁷ is oxygen; and optionally effecting one or more of the following conversions in any desired order: (i) converting a compound of formula (I) into a different compound of formula (I); (ii) converting a compound of formula (I) in to a pharmaceutically acceptable salt or N-oxide thereof; (iii) converting a pharmaceutically acceptable salt or N-oxide of a compound of formula (I) into the parent compound of formula (I); (iv) preparing a stereochemical isomeric form of a compound of formula (I) or a pharmaceutically acceptable salt or N-oxide thereof.
 9. A compound according to any of claims 1 to 7 for use as a medicine.
 10. A compound according to claim 9 for use in inhibiting tumor growth.
 11. A method for inhibiting tumor growth by administering an effective amount of a compound according to claim 1 to a subject, in need of such treatment. 